Metabolic syndrome refers to syndrome involving health risk factors such as hypertriglyceridemia, hypertension, glycometabolism disorder, blood coagulation disorder and obesity. Metabolic syndrome itself is not fatal, but indicates a predisposition to severe diseases such as diabetes and ischemic cardiovascular diseases, and has emerged as the most threatening diseases among modern people. Metabolic syndrome was once known by various other names including Syndrome X, due to lack of knowledge about causes of such syndrome, but was officially designated as Metabolic Syndrome or Insulin Resistance Syndrome through Adult Treatment Program III (ATP III) enacted by the WHO and the National Heart, Lung, and Blood Institute of the NIH.
The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), published in 2001, are the most current and widely used for diagnosing the metabolic syndrome. According to the ATP III criteria, individuals are diagnosed with the metabolic syndrome by the presence of three or more of these components: 1) A waistline of 40 inches (102 cm) or more for men and 35 inches (88 cm) or more for women (central obesity as measured by waist circumference), 2) A triglyceride level above 150 mg/dl, 3) A high density lipoprotein level (HDL) less than 40 mg/dl (men) or under 50 mg/dl (women), 4) A blood pressure of 130/85 mm Hg or higher and 5) A fasting blood glucose (sugar) level greater than 110 mg/dl. For eastern people, the criteria for central obesity was slightly adjusted to a waistline of 90 cm or more for men and 80 cm or more for women. Recent research has reported that under such criteria, around 25% of Korean people suffer from metabolic syndrome. Insulin resistance refers to a phenomenon wherein, even though insulin is normally secreted in vivo, insulin does not induce sufficient supply of glucose to cells. Therefore, glucose in the blood cannot enter cells, thus causing hyperglycemia, and thereby cells cannot perform normal functions due to a shortage of glucose, leading to the manifestation of metabolic syndrome.
At present, there are no drugs available for the treatment of metabolic syndrome. Attempts have been made to treat metabolic syndrome using therapeutic agents for diabetes, hyperlipidemia and hypertension, but these drugs have limited effectiveness in treating metabolic syndrome as the drug. As currently available drugs, metformin, drugs belonging to the TZD (thiazolidinediones) family, glucosidase inhibitors, dual PPARγ/α agonists and DDP (Dipeptidyl peptidase) IV inhibitors, which are used for the treatment of diabetes, have received a great deal of attention as promising drugs for treating metabolic syndrome. In addition, a great deal of interest has been directed to isoforms of apo A-I and related peptides thereof, which are targets of anti-blood pressure drugs and anti-hyperlipidemic drugs, and CETP (Cholesterol ester transport protein) inhibitors.
Known factors that are directly or indirectly associated with causes and treatment of metabolic syndrome include physical exercise, dietary habit and type, body weight, blood glucose, triglyceride levels, cholesterol levels, insulin resistance, adiponectin, leptin, AMPK activity, sex hormones such as estrogen, genetic factors and in vivo malonyl-CoA concentration.
At present, the most effective way to fight the conditions associated with metabolic syndrome is known to be getting more exercise and losing weight, and dietary control. All of the current ways of fighting metabolic syndrome share in common the fact that they facilitate energy metabolism, thus resulting in maximized consumption of surplus energy in the body leading to prevention of energy accumulation. Due to high calorie intake from processed foods and fast foods, compared to insufficient exercise, surplus energy is accumulated in the form of fat and thereby becomes an underlying cause of various diseases including metabolic disorders. Effectively eliminating such surplus energy is considered a method for treating metabolic disorders. Increasing metabolic activity is essential to effectively eliminate surplus energy. For this purpose, it is believed that there is an essential need for inhibition of fat synthesis, inhibition of gluconeogenesis, facilitation of glucose consumption, facilitation of fat oxidation, facilitation of biogenesis of mitochondria which is a central apparatus of energy metabolism and activation of factors involved in metabolism activation. Activation factors linked to promotion of metabolism include, for example, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), glucose transporter 1 and 4 (GLUT 1 and 4), carnitine palmitoyltransferase 1 (CPT 1), uncoupling protein 1, 2 and 3 (UCP-1, 2 and 3), and acetyl-CoA carboxylase I and II (ACC I and II), which play an important role in energy metabolism.
Such factors perform the following main functions in energy metabolism, in relation to metabolic disorders.
1. Glycometabolism
In muscle tissues and myocardial tissues, AMPK promotes muscle contraction and thereby facilitates uptake of glucose, which in turn activates GLUT 1, or induces migration of GLUT 4 to a plasma membrane, regardless of insulin action, resulting in increased transport of glucose into cells (Arch. Biochem. Biophys. 380, 347-352, 2000, J. Appl. Physiol. 91, 1073-1083, 2001). After increase of glucose uptake, AMPK activates hexokinase, thereby increasing flux of glycometabolism processes and simultaneously inhibiting glycogen synthesis. It is known that in myocardial tissues during ischemia, AMPK activates 6-phosphofructo-2-kinase (PFK-2) via a phosphorylation process, thus resulting in activation of a metabolic cascade leading to increased flux of glycometabolism (Curr. Biol. 10, 1247-1255, 2000). In addition, activation of AMPK in the liver inhibits release of glucose from hepatocytes. Meanwhile, it was confirmed that activity of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, which are enzymes of gluconeogenesis, was arrested by AMPK (Diabetes 49, 896-903, 2000), indicating that AMPK independently inhibits release of glucose from the liver, regardless of insulin, thus being involved in modulation of blood glucose level.
2. Mitochondrial Biogenesis
One important function of mitochondria is to carry out oxidative phosphorylation, which converts energy produced from fuel metabolites such as glucose and fatty acids into ATP. Functional mitochondrial alterations may effect pathogenesis of degenerative diseases associated with senescence, such as diabetes mellitus, cardiovascular diseases, Parkinson's disease and senile dementia (Curr. Opin. Cell Biol. 15, 706-716, 2003). Peterson, et al (Science 300, 1140-1142, 2003) has reported that oxidative phosphorylation functions of mitochondria were weakened by about 40% in the elderly, suggesting the possibility that deteriorated mitochondrial function is a probable pathogenic cause of insulin resistance syndrome. Lee et al (Diabetes Res. Clin. Pract. 42, 161-167, 1998) have confirmed that decreased mitochondrial DNA content in peripheral blood precedes the development of diabetes mellitus. Biogenesis of mitochondria in muscles is known to be promoted by an adaptive reaction in which metabolic activity of oxidative phosphorylation of muscle cells is increased by continuous energy depletion and exercise.
Meanwhile, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is known to be a co-activator promoting transcription of nuclear DNA and is known to play important roles in glucose metabolism, mitochondrial biogenesis, muscle fiber specialization and adaptive thermogenesis as main functions. It was confirmed that increased expression of PGC-1α facilitates an increase in the copy number of mitochondrial DNA and mitochondrial proliferation (Cell, 98, 115-124, 1999).
It was suggested that overexpression of UCP-2 and UCP-3 in the mouse model results in a decreased number of adipocytes, increased metabolic rate and increased oxygen consumption, and thus UCP-2 and UCP-3 play an important role in energy metabolism and obesity control (Nutrition, 20, 139-144, 2004).
3. Control of Fat Metabolism
Referring to a mechanism in which AMPK participates in fat metabolism, AMPK is known to induce phosphorylation of acetyl-CoA carboxylase which in turn inhibits fatty acid synthesis, thus resulting in decreased intracellular concentrations of malonyl-CoA that is an intermediate in a fatty acid synthesis process and is an inhibitor of carnitine palmitoyltransferase I (CPT I), leading to promotion of fatty acid oxidation. CPT I is an enzyme essential for a process wherein fatty acids enter mitochondria and are oxidized, and is known to be modulated by intracellular concentration of malonyl-CoA. In addition, AMPK is known to inhibit activity of HMG-CoA reductase and glycerol phosphate acyl transferase (GPAT), involved in cholesterol and triacylglycerol synthesis, through phosphorylation (J. Biol. Chem. 277, 32571-32577, 2002, Appl. Physiol. 92, 2475-2482, 2002). Meanwhile, it was found that activation of AMPK in the liver inhibits the activity of pyruvate kinase, fatty acid synthase and ACC through phosphorylation of carbohydrate-response-element-binding protein (ChREBP) (J. Biol. Chem. 277, 3829-3835, 2002).
As described above, activators related to metabolism are known to play central roles in energy metabolism of glucose, protein, and fat in vitro and in vivo. Neil et al (Nature drug discovery, 3(April), 340, 2004) asserted that AMPK and Malonyl-CoA are targets for therapeutic treatment of metabolic syndrome, and patients suffering from metabolic syndrome are characterized by insulin resistance, obesity, hypertension, dyslipidemia, and dysfunction of pancreatic beta cells, type I diabetes mellitus and manifestation of arteriosclerosis. It was hypothesized that a common feature linking these multiple abnormalities is dysregulation of AMPK/Malonyl-CoA fuel-sensing and signaling network. It was proposed that such dysregulation leads to alterations in cellular fatty-acid metabolism that in turn cause abnormal lipid accumulation, cellular dysfunction and ultimately disease. Evidence is also presented that factors that activate AMPK and/or reduce malonyl-CoA levels might reverse these abnormalities and syndromes or prevent them from occurring.
Genevieve et al (J. Biol. Chem. 279, 20767-74, 2004) have reported that activation of AMPK inhibits activity of an iNOS enzyme that is a inflammation mediator in chronic inflammatory conditions or endotoxin shock, including obesity-related diabetes and thus will be effective for developing new medicines having a mechanism capable of enhancing insulin sensitivity. In addition, they have reported that inhibition of iNOS activity is effected by activation of AMPK, and thus this finding is clinically applicable to diseases such as septicemia, multiple sclerosis, myocardial infarction, inflammatory bowel diseases and pancreatic beta-cell dysfunction. Zing-ping et al (FEBS Letters 443, 285-289, 1999) have reported that AMPK activates endothelial NO synthase through phosphorylation, in the presence of Ca-calmodulin in muscle cells and myocardial cells of rats. This represents that AMPK is implicated in cardiac diseases including angina pectoris. Alan D et al (Nature genetics, 34(3), 244, 2003) have confirmed that muscle mitochondrial respiratory metabolism was reduced by ageing or diabetes, thus resulting in coordinated changes in expression of genes involved in the oxidative phosphorylation process, and they have reported that PGC-1α is in charge of this change in gene expression. Mary et al (PNAS 100, 8466, 2003) have reported that decreased expression of PGC-1α is a main cause of insulin resistance and dysmetabolism in diabetic patients. Isabella et al (Am. J. Physiol. Cell Physiol. 284, c1669, 2003) have reported that PGC-1α is a key factor stimulating adaptation of mitochondria to changes in environment due to a thyroid hormone, T3, and muscle contraction. Kim et al (The Korean Journal of Biochemistry & Molecular Biology, 11, 16, 2004) have reported that through the causal relation between glucose/fatty acid metabolism, abnormalities in the amount and quality of mitochondria induces insulin resistance and furthermore, is a main cause of metabolic syndrome.
The present inventors carried out an extensive search for metabolism-activating drugs, based on the assumption that materials activating metabolism will be effective for treatment of metabolic syndrome diseases, and as a result, have confirmed that tanshinone derivatives are effective ingredients for therapeutic agents.